tbuckley/cabot-search huggingface dataset:
Fibroblast subsets in non-small cell lung cancer: Associations with survival, mutations, and immune features
Authors: Teijo Pellinen, Lassi Paavolainen, Alfonso Martín-Bernabé, Renata Papatella Araujo, Carina Strell, Artur Mezheyeuski, Max Backman, Linnea La Fleur, Oscar Brück, Jonas Sjölund, Erik Holmberg, Katja Välimäki, Hans Brunnström, Johan Botling, Pablo Moreno-Ruiz, Olli Kallioniemi, Patrick Micke, Arne Östman
Journal: JNCI Journal of the National Cancer Institute (2022)

Cancer-associated fibroblasts (CAFs) are molecularly heterogeneous mesenchymal cells that interact with malignant cells and immune cells and confer anti- and protumorigenic functions. Prior in situ profiling studies of human CAFs have largely relied on scoring single markers, thus presenting a limited view of their molecular complexity. Our objective was to study the complex spatial tumor microenvironment of non-small cell lung cancer (NSCLC) with multiple CAF biomarkers, identify novel CAF subsets, and explore their associations with patient outcome.Multiplex fluorescence immunohistochemistry was employed to spatially profile the CAF landscape in 2 population-based NSCLC cohorts (n = 636) using antibodies against 4 fibroblast markers: platelet-derived growth factor receptor-alpha (PDGFRA) and -beta (PDGFRB), fibroblast activation protein (FAP), and alpha-smooth muscle actin (αSMA). The CAF subsets were analyzed for their correlations with mutations, immune characteristics, and clinical variables as well as overall survival.Two CAF subsets, CAF7 (PDGFRA-/PDGFRB+/FAP+/αSMA+) and CAF13 (PDGFRA+/PDGFRB+/FAP-/αSMA+), showed statistically significant but opposite associations with tumor histology, driver mutations (tumor protein p53 [TP53] and epidermal growth factor receptor [EGFR]), immune features (programmed death-ligand 1 and CD163), and prognosis. In patients with early stage tumors (pathological tumor-node-metastasis IA-IB), CAF7 and CAF13 acted as independent prognostic factors.Multimarker-defined CAF subsets were identified through high-content spatial profiling. The robust associations of CAFs with driver mutations, immune features, and outcome suggest CAFs as essential factors in NSCLC progression and warrant further studies to explore their potential as biomarkers or therapeutic targets. This study also highlights multiplex fluorescence immunohistochemistry-based CAF profiling as a powerful tool for the discovery of clinically relevant CAF subsets.
Data-driven causal model discovery and personalized prediction in Alzheimer's disease
Authors: Haoyang Zheng, Jeffrey R. Petrella, P. Murali Doraiswamy, Guang Lin, Wenrui Hao
Journal: npj Digital Medicine (2022)

With the explosive growth of biomarker data in Alzheimer's disease (AD) clinical trials, numerous mathematical models have been developed to characterize disease-relevant biomarker trajectories over time. While some of these models are purely empiric, others are causal, built upon various hypotheses of AD pathophysiology, a complex and incompletely understood area of research. One of the most challenging problems in computational causal modeling is using a purely data-driven approach to derive the model's parameters and the mathematical model itself, without any prior hypothesis bias. In this paper, we develop an innovative data-driven modeling approach to build and parameterize a causal model to characterize the trajectories of AD biomarkers. This approach integrates causal model learning, population parameterization, parameter sensitivity analysis, and personalized prediction. By applying this integrated approach to a large multicenter database of AD biomarkers, the Alzheimer's Disease Neuroimaging Initiative, several causal models for different AD stages are revealed. In addition, personalized models for each subject are calibrated and provide accurate predictions of future cognitive status.
Early Versus Delayed Non–Vitamin K Antagonist Oral Anticoagulant Therapy After Acute Ischemic Stroke in Atrial Fibrillation (TIMING): A Registry-Based Randomized Controlled Noninferiority Study
Authors: Jonas Oldgren, Signild Åsberg, Ziad Hijazi, Per Wester, Maria Bertilsson, Bo Norrving
Journal: Circulation (2022)

There are no evidence-based recommendations on the optimal time point to initiate non-vitamin K antagonist oral anticoagulants (NOACs) after acute ischemic stroke in patients with atrial fibrillation. We aimed to investigate the efficacy and safety of early versus delayed initiation of NOAC in these patients.
Breast cancer: an up‐to‐date review and future perspectives
Authors: Ruoxi Hong, Binghe Xu
Journal: Cancer Communications (2022)

Breast cancer is the most common cancer worldwide. The occurrence of breast cancer is associated with many risk factors, including genetic and hereditary predisposition. Breast cancers are highly heterogeneous. Treatment strategies for breast cancer vary by molecular features, including activation of human epidermal growth factor receptor 2 (HER2), hormonal receptors (estrogen receptor [ER] and progesterone receptor [PR]), gene mutations (e.g., mutations of breast cancer 1/2 [BRCA1/2] and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [PIK3CA]) and markers of the immune microenvironment (e.g., tumor-infiltrating lymphocyte [TIL] and programmed death-ligand 1 [PD-L1]). Early-stage breast cancer is considered curable, for which local-regional therapies (surgery and radiotherapy) are the cornerstone, with systemic therapy given before or after surgery when necessary. Preoperative or neoadjuvant therapy, including targeted drugs or immune checkpoint inhibitors, has become the standard of care for most early-stage HER2-positive and triple-negative breast cancer, followed by risk-adapted post-surgical strategies. For ER-positive early breast cancer, endocrine therapy for 5-10 years is essential. Advanced breast cancer with distant metastases is currently considered incurable. Systemic therapies in this setting include endocrine therapy with targeted agents, such as CDK4/6 inhibitors and phosphoinositide 3-kinase (PI3K) inhibitors for hormone receptor-positive disease, anti-HER2 targeted therapy for HER2-positive disease, poly(ADP-ribose) polymerase inhibitors for BRCA1/2 mutation carriers and immunotherapy currently for part of triple-negative disease. Innovation technologies of precision medicine may guide individualized treatment escalation or de-escalation in the future. In this review, we summarized the latest scientific information and discussed the future perspectives on breast cancer.
Time to Optimize Deescalation Strategies in Triple-Negative Breast Cancer?
Authors: Priyanka Sharma
Journal: Clinical Cancer Research (2022)

Pathologic response serves as a tool to optimize escalation and deescalation of adjuvant treatment. Neoadjuvant carboplatin-taxane combination is a promising chemotherapy deescalation strategy for triple-negative breast cancer. Many key points, such as trial design/patient selection, response biomarkers, role of immunotherapy, and patient advocate input, will have to be carefully considered in order to advance neoadjuvant chemotherapy deescalation investigations. See related article by Gluz et al., p. 4995.
High throughput genome scale modeling predicts microbial vitamin requirements contribute to gut microbiome community structure
Authors: Juan P. Molina Ortiz, Mark Norman Read, Dale David McClure, Andrew Holmes, Fariba Dehghani, Erin Rose Shanahan
Journal: Gut Microbes (2022)

Human gut microbiome structure and emergent metabolic outputs impact health outcomes. However, what drives such community characteristics remains underexplored. Here, we rely on high throughput genomic reconstruction modeling, to infer the metabolic attributes and nutritional requirements of 816 gut strains, via a framework termed GEMNAST. This has been performed in terms of a group of human vitamins to examine the role vitamin exchanges have at different levels of community organization. We find that only 91 strains can satisfy their vitamin requirements (prototrophs) while the rest show various degrees of auxotrophy/specialization, highlighting their dependence on external sources, such as other members of the microbial community. Further, 79% of the strains in our sample were mapped to 11 distinct vitamin requirement profiles with low phylogenetic consistency. Yet, we find that human gut microbial community enterotype indicators display marked metabolic differences. Prevotella strains display a metabolic profile that can be complemented by strains from other genera often associated with the Prevotella enterotype and agrarian diets, while Bacteroides strains occupy a prototrophic profile. Finally, we identify pre-defined interaction modules (IMs) of gut species from human and mice predicted to be driven by, or highly independent of vitamin exchanges. Our analysis provides mechanistic grounding to gut microbiome stability and to co-abundance-based observations, a fundamental step toward understanding emergent processes that influence health outcomes. Further, our work opens a path to future explorations in the field through applications of GEMNAST to additional nutritional dimensions.
Rapid increase in neuroinvasive West Nile virus infections in humans, Italy, July 2022
Authors: Flavia Riccardo, Antonino Bella, Federica Monaco, Federica Ferraro, Daniele Petrone, Alberto Mateo-Urdiales, Xanthi D Andrianou, Martina Del Manso, Giulietta Venturi, Claudia Fortuna, Marco Di Luca, Francesco Severini, Maria Grazia Caporali, Daniela Morelli, Federica Iapaolo, Ilaria Pati, Letizia Lombardini, Tamas Bakonyi, Olivia Alexandra, Patrizio Pezzotti, Maria Gabriella Perrotta, Francesco Maraglino, Giovanni Rezza, Anna Teresa Palamara
Journal: Eurosurveillance (2022)

As in 2018, when a large West Nile virus (WNV) epidemic occurred, the 2022 vector season in Italy was marked by an early onset of WNV circulation in mosquitoes and birds. Human infections were limited until early July, when we observed a rapid increase in the number of cases. We describe the epidemiology of human infections and animal and vector surveillance for WNV and compare the more consolidated data of June and July 2022 with the same period in 2018.
Risk stratification and early detection biomarkers for precision HCC screening
Authors: Yi‐Te Lee, Naoto Fujiwara, Ju Dong Yang, Yujin Hoshida
Journal: Hepatology (2022)

Abstract Hepatocellular carcinoma (HCC) mortality remains high primarily due to late diagnosis as a consequence of failed early detection. Professional societies recommend semi‐annual HCC screening in at‐risk patients with chronic liver disease to increase the likelihood of curative treatment receipt and improve survival. However, recent dynamic shift of HCC etiologies from viral to metabolic liver diseases has significantly increased the potential target population for the screening, whereas annual incidence rate has become substantially lower. Thus, with the contemporary HCC etiologies, the traditional screening approach might not be practical and cost‐effective. HCC screening consists of (i) definition of rational at‐risk population, and subsequent (ii) repeated application of early detection tests to the population at regular intervals. The suboptimal performance of the currently available HCC screening tests highlights an urgent need for new modalities and strategies to improve early HCC detection. In this review, we overview recent developments of clinical, molecular, and imaging‐based tools to address the current challenge, and discuss conceptual framework and approaches of their clinical translation and implementation. These encouraging progresses are expected to transform the current “one‐size‐fits‐all” HCC screening into individualized precision approaches to early HCC detection and ultimately improve the poor HCC prognosis in the foreseeable future.
MAP7D2 reduces CD8+ cytotoxic T lymphocyte infiltration through MYH9-HMGB1 axis in colorectal cancer
Authors: Qian Wu, Xiao Yue, Huashan Liu, Yaxi Zhu, Haoxian Ke, Xin Yang, Shi Yin, Zhihao Li, Yunfeng Zhang, Tuo Hu, Ping Lan, Xianrui Wu
Journal: Molecular Therapy (2022)

Immune checkpoint inhibitors (ICIs) represent a new paradigm in cancer immunotherapy, but can be largely restricted by the limited presence of CD8+ cytotoxic T lymphocytes (CTLs) in colorectal cancer (CRC) patients with microsatellite stable (MSS) tumors. Here, through next-generation sequencing, we identify microtubule-associated protein 7 domain 2 (MAP7D2) as an exploitable therapeutic maneuver to improve the efficacy of ICIs for MSS CRC therapy. In human CRC tissues, MAP7D2 expression is significantly increased in MSS CRC, and MAP7D2 adversely correlates with the presence of antitumor T lymphocytes. In vitro and in vivo experiments demonstrate that MAP7D2 knockdown significantly increases the infiltration of CD8+ CTLs, thereby inhibiting tumor progression and improving the efficacy of ICIs in MSS CRC murine models. Mechanistically, MAP7D2 interacts with MYH9 and protects it from ubiquitin-mediated degradation, subsequently decreasing the secretion of HMGB1, which suppresses the infiltration of CD8+ CTLs in MSS CRC. These findings highlight the importance of MAP7D2 in determining the infiltration of CD8+ CTLs and indicate that targeting MAP7D2 in MSS CRC may present a novel antitumor immunotherapy. Immune checkpoint inhibitors (ICIs) represent a new paradigm in cancer immunotherapy, but can be largely restricted by the limited presence of CD8+ cytotoxic T lymphocytes (CTLs) in colorectal cancer (CRC) patients with microsatellite stable (MSS) tumors. Here, through next-generation sequencing, we identify microtubule-associated protein 7 domain 2 (MAP7D2) as an exploitable therapeutic maneuver to improve the efficacy of ICIs for MSS CRC therapy. In human CRC tissues, MAP7D2 expression is significantly increased in MSS CRC, and MAP7D2 adversely correlates with the presence of antitumor T lymphocytes. In vitro and in vivo experiments demonstrate that MAP7D2 knockdown significantly increases the infiltration of CD8+ CTLs, thereby inhibiting tumor progression and improving the efficacy of ICIs in MSS CRC murine models. Mechanistically, MAP7D2 interacts with MYH9 and protects it from ubiquitin-mediated degradation, subsequently decreasing the secretion of HMGB1, which suppresses the infiltration of CD8+ CTLs in MSS CRC. These findings highlight the importance of MAP7D2 in determining the infiltration of CD8+ CTLs and indicate that targeting MAP7D2 in MSS CRC may present a novel antitumor immunotherapy.
Neutralization of SARS-CoV-2 Omicron BA.2.75 after mRNA-1273 Vaccination
Authors: Xiaoying Shen, Spyros Chalkias, Jing Feng, Xing Chen, Honghong Zhou, Jean-Claude Marshall, Bethany Girard, Joanne E Tomassini, Anne Aunins, Rituparna Das, David C Montefiori
Journal: New England Journal of Medicine (2022)

ened neutralization escape.Overall, vaccine efficacy against BA.2.75 is expected to be similar to that against BA.1 and BA.2.Whether and by how much another vaccine booster, particularly one containing an omicron spike, would elicit a more potent response against BA.2.75 and future SARS-CoV-2 variants remains of high interest for vaccine development.
Scalable, ultra-fast, and low-memory construction of compacted de Bruijn graphs with Cuttlefish 2
Authors: Jamshed Khan, Marek Kokot, Sebastian Deorowicz, Rob Patro
Journal: Genome biology (2022)

The de Bruijn graph is a key data structure in modern computational genomics, and construction of its compacted variant resides upstream of many genomic analyses. As the quantity of genomic data grows rapidly, this often forms a computational bottleneck. We present Cuttlefish 2, significantly advancing the state-of-the-art for this problem. On a commodity server, it reduces the graph construction time for 661K bacterial genomes, of size 2.58Tbp, from 4.5 days to 17-23 h; and it constructs the graph for 1.52Tbp white spruce reads in approximately 10 h, while the closest competitor requires 54-58 h, using considerably more memory.
Multi-species meta-analysis identifies transcriptional signatures associated with cardiac endothelial responses in the ischaemic heart
Authors: Ziwen Li, Emmanouil G Solomonidis, Bronwyn Berkeley, Michelle Nga Huen Tang, Katherine Ross Stewart, Daniel Perez-Vicencio, Ian R McCracken, Ana-Mishel Spiroski, Gillian A Gray, Anna K Barton, Stephanie L Sellers, Paul R Riley, Andrew H Baker, Mairi Brittan
Journal: Cardiovascular Research (2022)

Abstract Aim Myocardial infarction remains the leading cause of heart failure. The adult human heart lacks the capacity to undergo endogenous regeneration. New blood vessel growth is integral to regenerative medicine necessitating a comprehensive understanding of the pathways that regulate vascular regeneration. We sought to define the transcriptomic dynamics of coronary endothelial cells following ischaemic injuries in the developing and adult mouse and human heart and to identify new mechanistic insights and targets for cardiovascular regeneration. Methods and results We carried out a comprehensive meta-analysis of integrated single-cell RNA-sequencing data of coronary vascular endothelial cells from the developing and adult mouse and human heart spanning healthy and acute and chronic ischaemic cardiac disease. We identified species-conserved gene regulatory pathways aligned to endogenous neovascularization. We annotated injury-associated temporal shifts of the endothelial transcriptome and validated four genes: VEGF-C, KLF4, EGR1, and ZFP36. Moreover, we showed that ZFP36 regulates human coronary endothelial cell proliferation and defined that VEGF-C administration in vivo enhances clonal expansion of the cardiac vasculature post-myocardial infarction. Finally, we constructed a coronary endothelial cell meta-atlas, CrescENDO, to empower future in-depth research to target pathways associated with coronary neovascularization. Conclusion We present a high-resolution single-cell meta-atlas of healthy and injured coronary endothelial cells in the mouse and human heart, revealing a suite of novel targets with great potential to promote vascular regeneration, and providing a rich resource for therapeutic development.
Variation in and Factors Associated With US County-Level Cancer Mortality, 2008-2019
Authors: Weichuan Dong, Wyatt P. Bensken, Uriel Kim, Johnie Rose, Qinjin Fan, Nicholas K. Schiltz, Nathan A. Berger, Siran M. Koroukian
Journal: JAMA Network Open (2022)

Importance The association between cancer mortality and risk factors may vary by geography. However, conventional methodological approaches rarely account for this variation. Objective To identify geographic variations in the association between risk factors and cancer mortality. Design, Setting, and Participants This geospatial cross-sectional study used county-level data from the National Center for Health Statistics for individuals who died of cancer from 2008 to 2019. Risk factor data were obtained from County Health Rankings &amp;amp;amp; Roadmaps, Health Resources and Services Administration, and Centers for Disease Control and Prevention. Analyses were conducted from October 2021 to July 2022. Main Outcomes and Measures Conventional random forest models were applied nationwide and by US region, and the geographical random forest model (accounting for local variation of association) was applied to assess associations between a wide range of risk factors and cancer mortality. Results The study included 7 179 201 individuals (median age, 70-74 years; 3 409 508 women [47.5%]) who died from cancer in 3108 contiguous US counties during 2008 to 2019. The mean (SD) county-level cancer mortality rate was 177.0 (26.4) deaths per 100 000 people. On the basis of the variable importance measure, the random forest models identified multiple risk factors associated with cancer mortality, including smoking, receipt of Supplemental Nutrition Assistance Program (SNAP) benefits, and obesity. The geographical random forest model further identified risk factors that varied at the county level. For example, receipt of SNAP benefits was a high-importance factor in the Appalachian region, North and South Dakota, and Northern California; smoking was of high importance in Kentucky and Tennessee; and female-headed households were high-importance factors in North and South Dakota. Geographic areas with certain high-importance risk factors did not consistently have a corresponding high prevalence of the same risk factors. Conclusions and Relevance In this cross-sectional study, the associations between cancer mortality and risk factors varied by geography in a way that did not correspond strictly to risk factor prevalence. The degree to which other place-specific characteristics, observed and unobserved, modify risk factor effects should be further explored, and this work suggests that risk factor importance may be a preferable paradigm for selecting cancer control interventions compared with risk factor prevalence.
A large multi-country outbreak of monkeypox across 41 countries in the WHO European Region, 7 March to 23 August 2022
Authors: Aisling M Vaughan, Orlando Cenciarelli, Soledad Colombe, Luís Alves de Sousa, Natalie Fischer, Celine M Gossner, Jeff Pires, Giuditta Scardina, Gudrun Aspelund, Margarita Avercenko, Sara Bengtsson, Paula Blomquist, Anna Caraglia, Emilie Chazelle, Orna Cohen, Asuncion Diaz, Christina Dillon, Irina Dontsenko, Katja Kotkavaara, Mario Fafangel, Federica Ferraro, Richard Firth, Jannik Fonager, Christina Frank, Mireia G Carrasco, Kassiani Gkolfinopoulou, Marte Petrikke Grenersen, Bernardo R Guzmán Herrador, Judit Henczkó, Elske Hoornenborg, Derval Igoe, Maja Ilić, Klaus Jansen, Denisa-Georgiana Janță, Tone Bjordal Johansen, Ana Kasradze, Anders Koch, Jan Kyncl, João Vieira Martins, Andrew McAuley, Kassiani Mellou, Zsuzsanna Molnár, Zohar Mor, Joël Mossong, Alina Novacek, Hana Orlikova, Iva Pem Novosel, Maria K Rossi, Malgorzata Sadkowska-Todys, Clare Sawyer, Daniela Schmid, Anca Sîrbu, Klara Sondén, Arnaud Tarantola, Margarida Tavares, Marianna Thordardottir, Veronika Učakar, Catharina Van Ewijk, Juta Varjas, Anne Vergison, Roberto Vivancos, Karolina Zakrzewska, Richard Pebody, Joana M Haussig
Journal: Eurosurveillance (2022)

Following the report of a non-travel-associated cluster of monkeypox cases by the United Kingdom in May 2022, 41 countries across the WHO European Region have reported 21,098 cases and two deaths by 23 August 2022. Nowcasting suggests a plateauing in case notifications. Most cases (97%) are MSM, with atypical rash-illness presentation. Spread is mainly through close contact during sexual activities. Few cases are reported among women and children. Targeted interventions of at-risk groups are needed to stop further transmission.
Metabolic, behavioural, and psychosocial risk factors and cardiovascular disease in women compared with men in 21 high-income, middle-income, and low-income countries: an analysis of the PURE study
Authors: Marjan Walli-Attaei, Annika Rosengren, Sumathy Rangarajan, Yolandi Breet, Suraya Abdul-Razak, Wadeia Al Sharief, Khalid F Alhabib, Alvaro Avezum, Jephat Chifamba, Rafael Diaz, Rajeev Gupta, Bo Hu, Romaina Iqbal, Rosnah Ismail, Roya Kelishadi, Rasha Khatib, Xinyue Lang, Sidong Li, Patricio Lopez-Jaramillo, Viswanathan Mohan, Aytekin Oguz, Lia M Palileo-Villanueva, Katarzyna Poltyn-Zaradna, Sreelakshmi P R, Lakshmi V M Pinnaka, Pamela Serón, Koon Teo, Sejil T Verghese, Andreas Wielgosz, Karen Yeates, Rita Yusuf, Sonia S Anand, Salim Yusuf
Journal: The Lancet (2022)